Astronomical pacing of late Palaeocene to early Eocene global warming events.

At the boundary between the Palaeocene and Eocene epochs, about 55 million years ago, the Earth experienced a strong global warming event, the Palaeocene-Eocene thermal maximum. The leading hypothesis to explain the extreme greenhouse conditions prevalent during this period is the dissociation of 1,400 to 2,800 gigatonnes of methane from ocean clathrates, resulting in a large negative carbon isotope excursion and severe carbonate dissolution in marine sediments. Possible triggering mechanisms for this event include crossing a threshold temperature as the Earth warmed gradually, comet impact, explosive volcanism or ocean current reorganization and erosion at continental slopes, whereas orbital forcing has been excluded. Here we report a distinct carbonate-poor red clay layer in deep-sea cores from Walvis ridge, which we term the Elmo horizon. Using orbital tuning, we estimate deposition of the Elmo horizon at about 2 million years after the Palaeocene-Eocene thermal maximum. The Elmo horizon has similar geochemical and biotic characteristics as the Palaeocene-Eocene thermal maximum, but of smaller magnitude. It is coincident with carbon isotope depletion events in other ocean basins, suggesting that it represents a second global thermal maximum. We show that both events correspond to maxima in the approximately 405-kyr and approximately 100-kyr eccentricity cycles that post-date prolonged minima in the 2.25-Myr eccentricity cycle, implying that they are indeed astronomically paced.

CD16 polymorphisms and NK activation induced by monoclonal antibody-coated target cells.

CD16 and natural killer (NK) cells appear to play a central role in mediating the anti-tumor effects of monoclonal antibody (mAb) therapy, yet little is known about changes in NK cells that result from interaction of the NK cells with mAb-coated tumor cells under physiologic conditions. We developed a system using peripheral blood mononuclear cells (PBMCs) and either transformed B cells or breast cancer cells to assess how mAbs impact on NK cell phenotype. Rituximab, apolizumab and trastuzumab induced modulation of CD16 and upregulation of CD54 on NK cells when the appropriate target cells were present. Higher concentrations of mAb were needed to induce these changes on NK cells from subjects with the lower affinity CD16 polymorphism. Phenotypic changes were greater in NK cells from subjects with the higher affinity polymorphism even when saturating concentrations of mAb were used, demonstrating increased concentration of mAb can overcome some, but not all, of the influence CD16 polymorphisms have on NK activation. These studies provide a straightforward and easily reproducible technique to measure the ability of mAb-coated tumor cells to activate NK cells in vitro which should be particularly useful as mAbs with varying affinity for both target antigen and Fc receptor (FcR) are developed.

Inferred time- and temperature-dependent cation ordering in natural titanomagnetites.

Despite years of efforts to quantify cation distribution as a function of composition in the magnetite-ulvöspinel solid solution, important uncertainties remain about the dependence of cation ordering on temperature and cooling rate. Here we demonstrate that Curie temperature in a set of natural titanomagnetites (with some Mg and Al substitution) is strongly influenced by prior thermal history at temperatures just above or below Curie temperature. Annealing for 10(-1) to 10(3) h at 350-400 °C produces large and reversible changes in Curie temperature (up to 150 °C). By ruling out oxidation/reduction and compositional unmixing, we infer that the variation in Curie temperature arises from cation reordering, and Mössbauer spectroscopy supports this interpretation. Curie temperature is therefore an inaccurate proxy for composition in many natural titanomagnetites, but the cation reordering process may provide a means of constraining thermal histories of titanomagnetite-bearing rocks. Further, our theoretical understanding of thermoremanence requires fundamental revision when Curie temperature is itself a function of thermal history.

Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab.

Growing evidence indicates that the affinity of monoclonal antibodies (mAbs) for CD16 (FcgammaRIII) plays a central role in the ability of the mAb to mediate antitumor activity. We evaluated how CD16 polymorphisms, and mAb with modified affinity for target antigen and CD16, affect natural killer (NK) cell phenotype when CD20(+) malignant B cells were also present. The mAb consisted of rituximab (R), anti-CD20 with enhanced affinity for CD20 (AME-B), and anti-CD20 with enhanced affinity for both CD20 and CD16 (AME-D). Higher concentrations of mAb were needed to induce CD16 modulation, CD54 up-regulation, and antibody-dependent cellular cytotoxicity (ADCC) on NK cells from subjects with the lower affinity CD16 polymorphism. The dose of mAb needed to induce NK activation was lower with AME-D irrespective of CD16 polymorphism. At saturating mAb concentrations, peak NK activation was greater for AME-D. Similar results were found with measurement of CD16 modulation, CD54 up-regulation, and ADCC. These data demonstrate that cells coated with mAb with enhanced affinity for CD16 are more effective at activating NK cells at both low and saturating mAb concentrations irrespective of CD16 polymorphism, and they provide further evidence for the clinical development of such mAbs with the goal of improving clinical response to mAb.